In order to determine the memory character of gd T cells we first attempted to establish in vitro gd T cell memory formation assays using various stimulating agents. Immune memory responses of gd T cells in adult peripheral blood mononuclear cells (PBMCs) cultures as well as cord blood PBMCs were assessed based on activation status, cytokine produced, proliferative and cytotoxic activities. We observed a huge variability between healthy donors in terms of gd T cell responses to stimulation and indicating that gd T cells in some donors may develop trained immunity. To further investigate this observation we determined the formation of trained immunity by gd T cells in vivo. In order to address this question we took a part in a clinical trial performed at the Radboud University Medical Center in Nijmegen, Netherlands, where healthy volunteers were vaccinated with BCG. We looked at gd T cell memory responses to heterologous challenges before and weeks after vaccination. We found that gd T cell responses to infectious agents in terms of cytokine production were not enhanced by BCG vaccination. Therefore we concluded that human circulating gd T cells do not develop trained immunity and therefore do not contribute to the cross-protective effect of vaccines.
We did observe however a distinct cytokine production profile and therefore functional responses of gd T cell when PBMC cultures were incubated with different stimuli. For example primary stimulation with phosphoantigen results in functionally potent gd T cells upon restimulation while zolendronic acid stimulation results in compromised cytokine production by gd T cell upon rechallange indicating that the primary stimuli generate functionally different gd T cells. We are currently investigating epigenetic landscape of differentially challenged gd T cells at genome-wide scale using next generation sequencing based technologies.
The project was conveyed to the Life and Medical Sciences Institute (LIMES) members in the interview as well as a short article for the internal magazine LIMES Klaaf. Furthermore, the project was communicated to the broader public in a blog article “Marie Curie and her actions”, which was awarded the “IITB travel grant 3: Blog support”, at the Young Investigator’s Science Blog of the ImmunoSensation Cluster of Excellence. The results were disseminated in a form of poster on several scientific national and international conferences including: The New Frontiers in Innate Immunity and Inflammation 2018 in Cluj-Napoca, Romania, ImmunoSensation Days 2019 in Bonn, Germany as well as on The 4th International Trained Immunity Conference 2019 in Nijmegen, the Netherlands. The preliminary results of the project were also announced during an invited seminar “From epigenetics of alpha beta T cells to the memory of gamma delta T cells” by the Women in Science Committee of the LIMES institute as well as informal retreat of research groups focused on innate immune cell biology. The fellowship resulted in three review articles shared with coauthors and published in peer-reviewed journals:
1. Netea MG, Schlitzer A, Placek K, Joosten LAB, Schultze LS (2019) ‘Innate and adaptive immune memory: an evolutionary continuum.’ Cell Host Microbe 25: 13-26.
2. Placek K, Schultze LS, Netea MG (2019) ‘Immune memory characteristics of innate lymphoid cells.’ Curr Opin Infect Dis 32: 196-203.
3. Placek K, Schultze LS, Aschenbrenner AC (2019) ‘Epigenetic reprogramming of immune cells in injury, repair and resolution.’ J Clin Invest 129: 2994-3005.
The results of the project have been submitted to a peer-reviewed journal.
